Neuron-specific knockdown of solute carrier protein SLC25A46a induces locomotive defects, an abnormal neuron terminal morphology, learning disability, and shortened lifespan.

Various mutations in the gene have been reported in mitochondrial diseases that are sometimes classified as type 2 Charcot-Marie-Tooth disease, optic atrophy, and Leigh syndrome. Although human SLC25A46 is a well-known transporter that acts through the mitochondrial outer membrane, the relationship between neurodegeneration in these diseases and the loss-of-function of remains unclear. Two genes, ) and ) have been identified as candidate homologs of human . We previously characterized the phenotypes of pan-neuron-specific knockdown flies. In the present study, we developed pan-neuron-specific knockdown flies and examined their phenotypes. Neuron-specific knockdown resulted in reduced mobility in larvae as well as adults. An aberrant morphology for neuromuscular junctions (NMJs), such as a reduced synaptic branch length and decreased number and size of boutons, was observed in knockdown flies. Learning ability was also reduced in the larvae of knockdown flies. In knockdown flies, mitochondrial hyperfusion was detected in NMJ synapses together with the accumulation of reactive oxygen species and reductions in ATP. These phenotypes were very similar to those of knockdown flies, suggesting that dSLC25A46a and dSLC25A46b do not have redundant roles in neurons. Collectively, these results show that the depletion of SLC25A46a leads to mitochondrial defects followed by an aberrant synaptic morphology, resulting in locomotive defects and learning disability. Thus, the knockdown fly summarizes most of the phenotypes in patients with mitochondrial diseases, offering a useful tool for studying these diseases.